Project

About the project

Up to 70% of cardiovascular events are not prevented by current therapeutic regimens. In search for additional, innovative strategies, immune cells have been recognized as key players contributing to atherosclerotic plaque progression and destabilization. Particularly the role of innate immune cells is of major interest, following the recent paradigm shift that innate immunity, considered to be incapable of learning ability, does exhibit a memory feature transduced via epigenetic modulation. Compelling evidence shows that atherosclerotic factors promote immune cell migration by pre-activation of innate immune cells. In this project called REPROGRAM, we aim to prove that innate immune cell activation via epigenetic reprogramming perpetuates the upheld systemic inflammatory state in cardiovascular disease which is common in other chronic inflammatory diseases. This opens a new therapeutic area in which epigenetic modulation of innate immune cells effectively decreases systemic inflammation impacting on chronic inflammation as well as the development of co-morbidities. The integrated use of in vitro, ex vivo and in vivo studies, including cells, mice and patients, allows translation from in vitro mechanisms to diseases (molecule-to-man) and extrapolation to cohorts (man-to-mass), enabling us to demonstrate relevance and therapeutic potential of targeting trained immunity in cardiovascular and chronic inflammatory diseases. Enforced by the promising data in oncology, the future prospects for epigenetic interventions in cardiovascular and chronic inflammatory diseases are eminent, attested by the large residual cardiovascular disease burden and the huge societal impact of other chronic inflammatory diseases. The REPROGRAM consortium consisting of key opinion leaders in the field of cardiovascular (systems) biology, immunology, epigenetic therapies and rheumatoid arthritis, with a large intersectoral network, guarantees rapid translation of early mechanistic discoveries.

Scientific knowledge

Recent landmark papers in immunology have given rise to a paradigm shift by revealing that innate immune cells also exhibit a memory feature, orchestrated by epigenetic modifications. Transient exposure of innate immune cells to various atherogenic stimuli causes a prolonged pro-inflammatory state, previously considered to be restricted to the adaptive immune system. This prolonged hyperresponsive state of innate immune cells, called ‘trained immunity’, may bear direct relevance to atherosclerosis as well as other chronic inflammatory diseases. It also echoes the highly feared recurrent cardiovascular-events in the first months after an initial cardiovascular-event, attributed largely to persistent inflammatory activity. As active participants in arterial wall inflammation, ‘primed’ innate immune cells may represent promising therapeutic targets. Targeting innate immune cells is likely to also offer a wider therapeutic window compared to the adaptive immune system, since patients with innate immune deficiencies are much less prone to infectious complications compared to those with disturbances in the adaptive immune system.